The present invention relates to contrast agents for radiographic imaging.
Radiographic imaging is widely used for the detection and diagnosis of various disease states. Methods such as plain film radiography, fluoroscopy, and digital radiography are two-dimensional imaging techniques which involve the projection of X-rays through individuals in order to produce visual images. Different tissues, based on their electron density, attenuate X-rays to different degrees. Radiation which is projected through the individual is detected and used to create an image which reflects the electron density of tissues lying between the X-ray source and detector. Computed tomography is a cross-sectional imaging technique which utilizes a rotating X-ray beam source to pass X-rays through an individual at different angles, and can thereby produce images with excellent spatial resolution in three dimensions. Unfortunately, intrinsic tissue contrast with CT is limited. This is due primarily to the fact that many tissues are composed of elements of similar electron density.
To improve the ability to detect normal structures, and to identify abnormalities involving those structures, contrast enhancement using exogenously administered contrast agents is considered essential. Contrast agents currently available are radiopaque, low molecular weight, water soluble, organic molecules, such as salts of iodine-containing aromatic molecules (e.g., diatrizoate and metrizoate). These radiopaque contrast agents result in greater attenuation of X-rays than most normal tissues in the human body, and therefore can lead to increased tissue contrast. The agents are usually injected intravenously into patients. However, due to their small size, they exhibit only a transient intravascular phase before diffusing into the interstitial space, where they provide little useful tissue contrast. In order to effectively utilize these contrast agents, administration and imaging must be performed rapidly so that images are acquired prior to diffusion into the interstitial space.
One approach to develop agents that remain in the intravascular space for prolonged periods of time (blood pool agents) is to create molecules that are significantly larger than the currently used agents, and that cannot readily diffuse from the blood vessels to the interstitial space. Unfortunately, such agents have proved difficult to develop. One approach has been to utilize molecules such as diatrizoate or metrizoate adsorbed onto particles. See, e.g., European Patent No. 498,482. Higher molecular weight contrast agents formed by radical polymerization of iodine-containing aromatic molecules have also been described. See, e.g., Lopour, et al., Proc. of 34th IUPAC Int. Symposium on Macromolecules, 3-P18 (1992). However, these higher molecular weight contrast agents are often too large to be excreted via the kidney, and thus are not easily eliminated from the body.
Micelle-forming block copolymers containing hydrophilic and hydrophobic portions have been used for in vivo delivery of anti-cancer pharmaceuticals (reviewed in Kataoka, et al., J. Controlled Release, 24:119-132, 1993). These micelle-forming copolymers have the ability to dissociate into their constituent polymer chains, or unimers, upon appropriate dilution, which allows their excretion. Additionally, certain hydrophilic polymers are adapted for allowing blood circulation of linked residues for prolonged periods of time.